Carbon monoxide (CO) is endogenously produced by heme oxygenase (HO) and CO may be an important signaling molecule in the vasculature including cerebral vessels. Endothelium-derived hyperpolarization factor (EDHF) relaxes blood vessels and may predominate over nitric oxide (NO) in resistance sized vessels. EDHF may also help to preserve vascular function in disease conditions where NO is reduced. This proposal will examine the role of CO in EDHF-mediated dilation in cerebral arteries. My preliminary data demonstrate that inhibition of HO with Cr(lll) mesoporphyrin IX (CrMP) blocks EDHF-mediated dilation to DTP in the rat middle cerebral artery (MCA). In the rat MCA, CO itself is not a dilator, however, in the presence of CrMP, exogenous CO restores EDHF-mediated dilation. These data suggest that CO plays a permissive-like role in EDHF-mediated dilation. This proposal will examine conditions in which CO is important for vasodilation in the rat MCA and will begin to examine the mechanism by which CO influences EDHF-mediated dilation in the rat MCA. Thus, this proposal brings together, for the first time, two important fields of study, CO and EDHF. [unreadable] [unreadable]